EP0164571A2 - Sustained-release forms of alpha-(2,5-dimethoxy phenyl)-beta-glycinamidoethanol and process for their preparation - Google Patents
Sustained-release forms of alpha-(2,5-dimethoxy phenyl)-beta-glycinamidoethanol and process for their preparation Download PDFInfo
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- EP0164571A2 EP0164571A2 EP85105612A EP85105612A EP0164571A2 EP 0164571 A2 EP0164571 A2 EP 0164571A2 EP 85105612 A EP85105612 A EP 85105612A EP 85105612 A EP85105612 A EP 85105612A EP 0164571 A2 EP0164571 A2 EP 0164571A2
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- hydrochloride
- poly
- hydroxybutyric acid
- midodrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
- A61K9/204—Polyesters, e.g. poly(lactide-co-glycolide)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
Definitions
- the invention relates to oral sustained release forms of alpha- (2,5-dimethoxy-phenyl) -ß-glycinamidoethanol (midodrin) and a process for their preparation.
- sustained-release formulations are molded pharmaceutical articles which contain poly-D (-) - 3-hydroxybutyric acid with a specific molecular weight and a selected particle size as carrier material (matrix) and, after oral administration, the active substance in the gastrointestinal tract in a regulated manner deliver delayed.
- Midodrin alpha- (2,5-dimethoxy-phenyl-ß-glycinamidoethanol
- hydrochloride is a tried and tested active ingredient (DE-PS-1,493,917).
- the therapeutic effects of midodrin hydrochloride in sympathotonic and asympathetic hypotension have been confirmed many times in clinical studies.
- Midodrin hydrochloride unlike other known sympathomimetics that respond to alpha and beta receptors, acts selectively on the peripheral alpha receptors and is used in the therapy of constitutional and symptomatic hypotension For example, hypotonic states in infections, in convalescence, in operations and deliveries, further hypotonic lability in weather sensitivity and problems with blow-drying or morning start-up symptoms. In these clinical pictures, patients are known to suffer particularly strongly from the symptoms of H immediately after getting up in the first few hours of the morning ypotonie such as dizziness and weakness, headache, listlessness and so on.
- midodrine hydrochloride is in many cases the only effective known to date for patients suffering from the most severe forms of circulatory regulation disorders and malregulations, such as idiopathic orthostatic hypotension or Shy-Drager syndrome represents drug treatment.
- dazy Midodrine a new agent in the management of idiopathic orthostatic hypotension and Shy-Drager syndrome by Alexander Schirger at al published Mayo Clin. Proc., July 1981, Vol. 56, pages 429-433. Since patients with these chronic clinical pictures are dependent on long-term treatment with midodrin hydrochloride, a reduction in the number of intakes per day would improve the living situation of these patients, which is recognized as being important with long-term medication.
- sustained release forms can be prepared, for example, by formulating the active ingredient together with excipients in such a way that it is slowly released, for example by embedding it in a matrix that does not dissolve or only dissolves slowly.
- matrix systems such as with cellulose derivatives, polyvinyl acetate, polyethylene, polyvinyl chloride or polymethacrylate a good retardation of the active ingredient can be achieved, but the disadvantage must be accepted that such midodrine hydrochloride prolonged-release forms, the release of the initial dose is much too slow in the initial phase of medication.
- the solution to the problem according to the invention is that midodrine hydrochloride as an active ingredient in a certain weight ratio with a microbial fermentation-obtained poly-D (-) - 3-hydroxybutyric acid with a sufficiently high molecular weight and a certain, selected grain size fraction mixed and processed into compacts.
- the invention accordingly relates to oral prolonged-release forms of alpha- (2,5-dimethoxy-phenyl) -beta-glycinamidoethanol (midodrin) in the form of solid, molded pharmaceutical molded articles, consisting of the active ingredient, a polymer obtained by microbial route.
- the slow-release form is based on a part by weight of alpha- (2,5-dimethoxy-phenyl) -beta-glycinamido ethanol in the form of the hydrochloride (midodrine hydrochloride) contains 1 to 15 parts by weight of poly-D (-) - 3-hydroxybutyric acid with a molecular
- medicament shaped bodies for the slow-release forms according to the invention compacts in any size and shape that are suitable for oral administration, such as tablets, dragee cores, sticks and so on, come into consideration.
- other medicinal forms produced by pressing for example comminuted particles which are subsequently filled into capsules, or multilayer tablets or coated tablets, in which, in addition to the sustained-release layer, non-retarded active ingredients are to be contained, are also suitable for this purpose.
- Particularly preferred medicinal forms for the sustained-release preparations according to the invention are tablets which can be produced in a simple manner in a single operation and which represent a medicinal form which is familiar to the patient and is therefore particularly popular. These tablets can have one or more break grooves, which enable the patient to shred the tablet and to take the preparation in addition to the dosage units offered in the individual dose prescribed by the doctor or selected according to personal experience.
- the poly-D (-) - 3-hydroxybutyric acid (PHB) used as a pharmaceutical carrier and retardant is obtained by fermentation from the cell material of microorganisms of a prokaryotic nature, which are able to accumulate PHB inside the cell as a storage material for energy and carbon.
- PHB-storing microorganisms have now been detected in about 50 different types of bacteria in almost 150 different strains and can be found, for example, in phototrophic bacteria, gram-negative aerobic rods and cocci, gram-negative cocci and coccobacilli, gram-negative chemolithotrophic bacteria, endospore-forming rods and cocci, gram-positive asporogenic rod-shaped bacteria, methylotrophic bacteria, actinomycetan, budding or hanging bacteria, cyanobacteria and so on.
- the chemical structure of a PHB obtained from fermentation and isolation from microbial cell mass is that of a starchically uniform, chiral polymer, with about 600 to 30,000 repeat units being found.
- Polymers with a molecular weight of at least 50,000 to about 2,000,000 are suitable for the matrix forms according to the invention, polymers with a molecular weight of at least 50,000 to about 1,500,000 being particularly preferred.
- the fermentative production of PHB and isolation from the cell material has been described, for example, by Lafferty et al. in Chem. Rundschau 30 (41), 14 to 16, (1977).
- Midodrine hydrochloride sustained-release preparations with release rates which in any way meet the requirements given in points a) and b) above are only unexpectedly obtained when a poly-D (-) - 3-hydroxybutyric acid is used as the polymeric carrier for retardation a grain size of 0.05 to 0.6 mm, preferably with a grain size of 0.2 to 0.5 mm, and such mixtures of polymeric matrix and active ingredient are produced which are 1 to 15 parts by weight, but preferably 2 to 6 parts by weight, to 1 part by weight , very preferably contain 3 to 5 parts by weight of PHB. These mixtures are then pressed into the depot dosage forms according to the invention.
- Midodrin hydrochloride is a very effective drug that is administered to the patient in extremely low doses.
- the dose range for the slow release forms according to the invention is between 3.5 and 20 mg of midodrin hydrochloride per dose unit, but preferably between 7.5 and 15 mg. In individual cases of pathological forms of disease, a higher dose range per dose unit may exceptionally be appropriate for the slow-release form under medical supervision.
- Another object of the invention is a method for producing these midodrine hydrochloride sustained release forms.
- the PHB obtained from the biomass by fermentation and isolation is characterized by favorable physical properties such as low elastic properties and low electrostatic charging tendency, and also has good lubricating and glazing properties; Therefore, the slow release molds according to the invention can be produced in an unexpectedly simple manner, both from a technical and an apparatus point of view.
- the fermentation product is crushed by painting and the grain size fraction required for the production of the homogenate in the range from 0.05 to 0.6 mm is then obtained from the material to be painted by sieve analysis.
- the procedure according to the invention is such that the active ingredient is mixed mechanically with the PHB in the desired weight ratio and brought into a homogeneous form.
- the homogenization can expediently be carried out using a powder grater and pestle or a powder mixing can.
- Large batches can advantageously be homogenized with the help of rotating drums, cube mixers, paddle mixers, plate mixers, mixing screws, ribbon mixers, cone mixers, double cone mixers, V mixers (twin-shell orifices) or similar devices.
- the homogenates obtained in this way are then pressed according to a preferred process method directly into tablets, dragee cores, sticks or other compresses of any shape without further additives.
- the active ingredient can also be processed with PHB and, if desired, other direct-tablettable auxiliaries, lubricants, etc. to form a direct-tablettable mixture which is then pressed to give shaped pharmaceutical articles.
- the pressure can be varied over the range from 0.1 to about 10 tons / cm 2 , corresponding to 9.81 to 981 N / mm 2 , and depends on the type and shape of the compacts produced.
- the release rate of the active substance shows no significant dependence on the pressing pressure when the pressing pressure is varied in the range given above.
- the homogenate of active ingredient and PHB can also first be processed moist or dry into granules using one of the customary granulation processes, and these granules, if appropriate after the addition of additives customary in galenics, can be pressed to give shaped medicinal products.
- the active ingredient can also be converted into granules, to which the PHB is subsequently added, by means of wet and dry granulation, where appropriate, after which the mass is pressed to give shaped medicinal products.
- the use of such granulation processes includes an additional process step, but offers no significant advantage over the direct pressing of the homogenate.
- the simplicity with which optimal oral, solid midodrine hydrochloride prolonged release forms can be achieved according to the invention was not predictable. If one takes into account the difficulties which have hitherto existed in the retardation of midodrine hydrochloride and which occur with the previously known biodegradable matrix forms in the formulation of pharmaceutical forms, it is an unexpected result for a person skilled in the art that in the matrix system according to the invention by simple mixing and pressing can produce solid prolonged-release forms of midodrine hydrochloride with release rates that can be varied in almost any manner.
- the sustained release forms according to the invention also offer a further unexpected advantage in that within the first 20 to 60 minutes after administration, the initial dose of the active ingredient required to build up therapeutically effective blood level values is released directly from the matrix system.
- the preparations according to the invention can therefore dispense with additional measures which are intended to ensure the release of the initial dose, such as spraying, coating or coating the retard form with the active ingredient in instant form. In this way, the losses of active ingredient usually associated with such measures can be avoided and the manufacturing process can be simplified.
- a midodrine hydrochloride prolonged-release tablet according to the present invention which contains 7.5 mg gutron and 22.5 mg PHB with a grain size fraction of 0.2 to 0.315 mm and a molecular weight of 1.06 10 6 in a homogeneous mixture, has one hour after in vitro experiment Release rate of 47.33%, corresponding to 3.5 mg of midodrine hydrochloride, while after 7 hours the active ingredient is released from the prolonged-release form.
- In vivo experiments with the same midodrin hydrochloride prolonged-release tablet give similar release rates, for example 2 hours after administration 67.65% and 8 hours after administration are 96.18% of the amount of active ingredient initially present in the sustained-release form.
- the ingredients are sieved and mixed and homogenized in a cube mixer.
- the homogenate is pressed into tablets at a pressure of 3.2 tons / cm 2 , corresponding to 313.92 N / mm 2 .
- Tablet size diameter 4.0 mm, height 2.0 mm
- the tablets are administered orally to rats using a special probe and the amount of midodrin hydrochloride released at the times indicated (2,4,6,8 hours) is determined by residue determination.
- the animals are killed by slapping the neck and the tablets are removed from the gastrointestinal tract. After the tablets have been cleaned and dried, they are mechanically crushed, mixed with H 2 O and further treated in an ultrasonic bath to release midodrin hydrochloride completely. After centrifugation, midodrin hydrochloride is determined directly from the solution.
- the processing into tablets is carried out analogously to Example 1 under different compression pressures.
- the release rates are independent of the pressure in the range from 0.5 to 2.0 tons / cm 2 , with which the homogenate in Example 3 was pressed into tablets.
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Abstract
Description
Die Erfindung betrifft orale Retardformen des alpha-(2,5-Dimethoxy-phenyl)-ß-glycinamidoäthanols (Midodrin) und ein Verfahren zu deren Herstellung. Diese Retardformulierungen sind durch Verpressen hergestellte Arzneimittel- Formkörper, die Poly-D(-)-3-hydroxybuttersäure mit einem bestimmten Molekulargewicht und einer ausgewählten Korngröße als Trägermaterial (Matrix) enthalten und nach oraler Applikation den Wirkstoff im Magen-Darm-Trakt in geregelter Weise verzögert abgeben.The invention relates to oral sustained release forms of alpha- (2,5-dimethoxy-phenyl) -ß-glycinamidoethanol (midodrin) and a process for their preparation. These sustained-release formulations are molded pharmaceutical articles which contain poly-D (-) - 3-hydroxybutyric acid with a specific molecular weight and a selected particle size as carrier material (matrix) and, after oral administration, the active substance in the gastrointestinal tract in a regulated manner deliver delayed.
Bei Midodrin (alpha-(2,5-Dimethoxy-phenyl-ß-glycinamidoäthanol) und seinem Hydrochlorid handelt es sich um einen seit Jahren bewährten Wirkstoff (DE-PS-1,493.917). Die therapeutischen Wirkungen von Midodrin-Hydrochlorid bei sympathotoner und asympathotoner Hypotonie wurden in klinischen Untersuchungen vielfach bestätigt. Midodrin-Hydrochlorid wirkt zum Unterschied von anderen bekannten Sympathomimetika, die auf alpha- und ß-Rezeptoren ansprechen, selektiv auf die peripheren alpha-Rezeptoren und findet seinen Anwendungsbereich in der Therapie von konstitutioneller und symptomatischer Hypotonie. Anwendungsgebiete sind beispielsweise hypotone Zustände bei Infektionen, in der Rekonvaleszenz, bei Operationen und Entbindungen, weiters hypotone Labilität bei Wetterfühligkeit und Föhnbeschwerden oder morgendliche Startbeschwerden. Bei diesen Krankheitsbildern leiden die Patienten bekanntermaßen unmittelbar nach dem Aufstehen in den ersten Morgenstunden besonders stark unter den Symptomen der Hypotonie wie Schwindel- und Schwächegefühlen, Kopfschmerzen, Antriebslosigkeit und so weiter.Midodrin (alpha- (2,5-dimethoxy-phenyl-ß-glycinamidoethanol) and its hydrochloride is a tried and tested active ingredient (DE-PS-1,493,917). The therapeutic effects of midodrin hydrochloride in sympathotonic and asympathetic hypotension have been confirmed many times in clinical studies.Midodrin hydrochloride, unlike other known sympathomimetics that respond to alpha and beta receptors, acts selectively on the peripheral alpha receptors and is used in the therapy of constitutional and symptomatic hypotension For example, hypotonic states in infections, in convalescence, in operations and deliveries, further hypotonic lability in weather sensitivity and problems with blow-drying or morning start-up symptoms. In these clinical pictures, patients are known to suffer particularly strongly from the symptoms of H immediately after getting up in the first few hours of the morning ypotonie such as dizziness and weakness, headache, listlessness and so on.
Deshalb würden Retardformen von Midodrin-Hydrochlorid, welche den Wirkstoff nach der Einnahme des Medikaments am Vorabend so gleichmäßig und verzögert abgeben, daß therapeutische Blutspiegelwerte trotz des großen Einnahmemtervalls über Nacht bis zum nächsten Morgen aufrecht erhalten werden konnten, große Vorteile bieten, da dem Patienten auf diese Weise ein beschwerdefreies Aufstehen ermäglicht würde.Therefore, prolonged-release forms of midodrine hydrochloride, which release the active ingredient so evenly and with a delay after taking the medication the evening before that therapeutic blood level values could be maintained overnight until the next morning despite the large intake interval, would offer great advantages to the patient this would allow a trouble-free getting up.
Neuere Untersuchungen haben zudem ergeben, daß die Verabreichung von Midodrin-Hydrochlorid für Patienten, die unter schwersten Formen von Kreislaufregulationsstörungen und -fehlregulationen, wie beispielsweise der idiopathischen orthostatischen Hypotonie oder dem Shy-Drager-Syndrom, leiden, in vielen Fällen die einzige bisher bekannte wirksame medikamentöse Behandlung darstellt. (vgl dazy Midodrine, a new agent in the management of idiopathic orthostatic hypotension and Shy-Drager-syndrome von Alexander Schirger at al erschienen Mayo Clin. Proc., Juli 1981, Vol. 56, Seiten 429 - 433). Da Patienten mit diesen chronischen Krankheitsbildern von einer Dauerbehandlung mit Midodrin-Hydrocchlorid abhängig sind, würde eine Verringerung der Zahl der Einnähmen pro Tag die Lebenssituation dieser Patienten verbessern, was gerade hei einer Langzeitmedikation anerkanntermaßen von Bedeutung ist.Recent research has also shown that the administration of midodrine hydrochloride is in many cases the only effective known to date for patients suffering from the most severe forms of circulatory regulation disorders and malregulations, such as idiopathic orthostatic hypotension or Shy-Drager syndrome represents drug treatment. (cf. dazy Midodrine, a new agent in the management of idiopathic orthostatic hypotension and Shy-Drager syndrome by Alexander Schirger at al published Mayo Clin. Proc., July 1981, Vol. 56, pages 429-433). Since patients with these chronic clinical pictures are dependent on long-term treatment with midodrin hydrochloride, a reduction in the number of intakes per day would improve the living situation of these patients, which is recognized as being important with long-term medication.
Aufgrund dieser offensichtlichen Vorteile einer Retardform von Midodrin-Hydrochiorid hat es nicht an Versuchen zu ihrer Realisierung gefehlt. Pharmazeutische Retardformen können beispielsweise dadurch zubereitet werden, daß der Wirkstoff zusammen mit Hilfsstoffen so formuliert wird, daß er langsam freigegeben ird, z B. durch Einbetten in eine sich nicht oder nur langsam auflösende Matrix. Bei der Anwendung dieser Methode auf Midodrin-Hydrochlorid hat sich nun gezeigt, daß man mit bekannten Matrixsystemen wie mit Cellulosederivaten, Polyvinylacetat, Polyäthylen, Polyvinylchlorid oder Polymethacrylat zwar eine gute Retardierung des Wirkstoffs erreichen kann, aber dafür den Nachteil in Kauf nehmen muß, daß bei solchen Midodrin-Hydrochlorid-Retardformen die Freisetzung der lnitialdosis in der Anfangsphase der Medikation viel zu langsam erfolgt. Dieser Nachteil ließe sich nur durch die Bereitstellung von aufwendigeren Arzneiformen verringern, bei denen die als Initialdosis benötigte Wirkstoffmenge in der Instantform nachträglich auf die Retardform, beispielsweise durch Aufsprühen, aufgebracht wird. Die Herstellung solcher gemischter Arzneiformen ist aber technisch sehr aufwendig und führt regelmäßig zu nicht unerheblichen Wirkstoffverlusten.Because of these obvious advantages of a sustained release form of midodrine hydrochloride, there has been no shortage of attempts to implement it. Pharmaceutical sustained release forms can be prepared, for example, by formulating the active ingredient together with excipients in such a way that it is slowly released, for example by embedding it in a matrix that does not dissolve or only dissolves slowly. When using this method on midodrine hydrochloride it has now been shown that with known matrix systems such as with cellulose derivatives, polyvinyl acetate, polyethylene, polyvinyl chloride or polymethacrylate a good retardation of the active ingredient can be achieved, but the disadvantage must be accepted that such midodrine hydrochloride prolonged-release forms, the release of the initial dose is much too slow in the initial phase of medication. This disadvantage could only be reduced by the provision of more complex pharmaceutical forms, in which the amount of active substance required as an initial dose is subsequently added to the instant form Retard form, for example by spraying, is applied. However, the production of such mixed pharmaceutical forms is technically very complex and regularly leads to not inconsiderable loss of active ingredient.
Es ist nun unerwarteterweise gelungen, Midodrin-Hydrochlorid-Retardformen zu finden, bei denen eine ausreichende Initialdosis nach der Verabreichung direkt aus einer einheitlichen Retardform freigesetzt und ein lang anhaltender gleichmäßiger Midodrin-Hydrochlorid-Blutspiegel gewährleistet wird. Gleichzeitig haben diese Retardformen noch den Vorteil, daß sie auf einfache Weise in Form von üblichen oralen Arzneiformen z.B. Tabletten hergestellt werden können und bei der Arzneiformengebung die oben skizzierten Nachteile von bekannten Matrixformen nicht auftreten.It has now unexpectedly succeeded in finding midodrine hydrochloride prolonged release forms in which a sufficient initial dose is released directly from a uniform prolonged release form after administration and a long-lasting, uniform midodrin hydrochloride blood level is ensured. At the same time, these prolonged-release forms have the advantage that they can be easily obtained in the form of conventional oral dosage forms, e.g. Tablets can be produced and the disadvantages of known matrix forms outlined above do not occur in the formulation of pharmaceutical forms.
Die erfindungsgemäße Lösung des Problems besteht darin, daß man Midodrin-Hydrochlorid als Wirkstoff in einem bestimmten Gewichtsverhältnis mit einer auf mikrobiellem Weg durch Fermentation gewonnenen Poly-D(-)-3-hydroxy- buttersäure mit einem genügend hohen Molekulargewicht und einer bestimmten, ausgewählten Korngrößenfraktion vermischt und zu Preßlingen verarbeitet.The solution to the problem according to the invention is that midodrine hydrochloride as an active ingredient in a certain weight ratio with a microbial fermentation-obtained poly-D (-) - 3-hydroxybutyric acid with a sufficiently high molecular weight and a certain, selected grain size fraction mixed and processed into compacts.
Gegenstand der Erfindung sind demnach orale Retardformen des alpha-(2,5-Dimethoxy-phenyl)-beta-glycinamidoäthanols (Midodrin) in Form von festen, durch Verpressen hergestellten Arzneimittel-Formkörpern, bestehend aus dem Wirkstoff, einer auf mikrobiellen Weg gewonnenen Poly-D(-)-3-hydroxybutter- säure (PHB) und gegebenenfalls in der Galenk üblichen Hilfs- und Zusatzstoffen, dadurch gekennzeichnet, daß die Retardform auf einen Gew. Teil alpha-(2,5-Dimethoxy-phenyl)-beta-glycinamido-äthanol in Form des Hydrochlorids (Midodrin-Hydrochlorid) 1 bis 15 Gew. Teile Poly-D(-)-3-hydroxybuttersäure mit einem Molekulargewicht von mindestens 50000 und einer ausgewählten Korngrößenfraktion im Bereich von 0.05 bis 0.6 mm in homogener Mischung enthält.The invention accordingly relates to oral prolonged-release forms of alpha- (2,5-dimethoxy-phenyl) -beta-glycinamidoethanol (midodrin) in the form of solid, molded pharmaceutical molded articles, consisting of the active ingredient, a polymer obtained by microbial route. D (-) - 3-hydroxybutyric acid (PHB) and, if appropriate, auxiliaries and additives customary in galenk, characterized in that the slow-release form is based on a part by weight of alpha- (2,5-dimethoxy-phenyl) -beta-glycinamido ethanol in the form of the hydrochloride (midodrine hydrochloride) contains 1 to 15 parts by weight of poly-D (-) - 3-hydroxybutyric acid with a molecular weight of at least 50,000 and a selected particle size fraction in the range from 0.05 to 0.6 mm in a homogeneous mixture.
Als Arzneimittel-Formkörper für die erfindungsgemäßen Retardformen kommen Preßlinge in jeder Größe und Form, die für die orale Applikation geeignet sind, in Betracht, wie Tabletten, Drageekerne, Stäbchen und so weiter. Jedoch eignen sich für diesen Zweck auch andere durch Verpressen hergestellte Arzneiformen, beispielsweise zerkleinerte Komprimate, die anschließend in Kapseln abgefüllt werden, oder auch Mehrschichttabletten oder -dragees, bei denen neben der Retardschicht in einer anderen Schicht nichtretardierte Wirkstoffe enthalten sein sollen. Besonders bevorzugte Arzneiformen für die erfindungsgemäßen Retardpräparate sind Tabletten, die auf einfache Weise in einem einzigen Arbeitsgang hergestellt werden können und eine für den Patienten vertraute und dadurch besonders gern angenommene Arzneiform darstellen. Diese Tabletten können eine oder mehrere Bruchrillen aufweisen, die es dem Patienten ermöglichen die Tablette zu zerkleinern und das Präparat über die angebotenen Dosierungseinheiten hinaus in der vom Arzt verordneten oder nach eigener Erfahrung gewählten, individuellen Dosis zu sich zu nehmen.As medicament shaped bodies for the slow-release forms according to the invention, compacts in any size and shape that are suitable for oral administration, such as tablets, dragee cores, sticks and so on, come into consideration. However other medicinal forms produced by pressing, for example comminuted particles which are subsequently filled into capsules, or multilayer tablets or coated tablets, in which, in addition to the sustained-release layer, non-retarded active ingredients are to be contained, are also suitable for this purpose. Particularly preferred medicinal forms for the sustained-release preparations according to the invention are tablets which can be produced in a simple manner in a single operation and which represent a medicinal form which is familiar to the patient and is therefore particularly popular. These tablets can have one or more break grooves, which enable the patient to shred the tablet and to take the preparation in addition to the dosage units offered in the individual dose prescribed by the doctor or selected according to personal experience.
Die als Arzneimittelträger und Retardierungsmittel verwendete Poly-D(-)-3-hydroxybuttersäure (PHB) wird auf fermentativem Weg aus dem Zellmaterial von Mikroorganismen prokaryotischer Natur, welche imstande sind PHB zellintern als Speicherstoff für Energie und Kohlenstoff anzuhäufen, gewonnen. PHB-speichernde Mikroorganismen sind inzwischen in etwa 50 verschiedenen Arten von Bakterien bei fast 150 verschiedenen Stämmen nachgewiesen worden und finden sich beispielsweise bei phototrophen Bakterien, gramnegativen aeroben Stäbchen und Kokken, gramnegativen Kokken und Kokkobacillen, gramnegativen chemolithothrophen Bakterien, Endosporen bildenden Stäbchen und Kokken, grampositiven asporogenen stäbchenförmigen Bakterien, methylotrophen Bakterien, Aktinomycetan, knospenden oder Anhängsel tragenden Bakterien, Cyanobakterien und so weiter. Die chemische Struktur einer durch Fermentation und Isolierung aus mikrobieller Zellmasse gewonnenen PHB ist die eines starisch einheitlichen, chiralen Polymeren, wobei etwa 600 bis 30000 Wiederholungseinheiten gefunden werden können. Für die erfindungsgemäßen Matrixformen eignen sich Polymeren mit einem Molekulargewicht von mindestens 50000 bis etwa 2,000.000, wobei Polymere mit einem Molekulargewicht von mindestens 50000 bis etwa 1,500.000 besonders bevorzugt sind. Die fermentative Herstellung von PHB und Isolierung aus dem Zellmaterial wurde beispielsweise von Lafferty et al. in Chem. Rundschau 30 (41), 14 bis 16, (1977) beschrieben.The poly-D (-) - 3-hydroxybutyric acid (PHB) used as a pharmaceutical carrier and retardant is obtained by fermentation from the cell material of microorganisms of a prokaryotic nature, which are able to accumulate PHB inside the cell as a storage material for energy and carbon. PHB-storing microorganisms have now been detected in about 50 different types of bacteria in almost 150 different strains and can be found, for example, in phototrophic bacteria, gram-negative aerobic rods and cocci, gram-negative cocci and coccobacilli, gram-negative chemolithotrophic bacteria, endospore-forming rods and cocci, gram-positive asporogenic rod-shaped bacteria, methylotrophic bacteria, actinomycetan, budding or hanging bacteria, cyanobacteria and so on. The chemical structure of a PHB obtained from fermentation and isolation from microbial cell mass is that of a starchically uniform, chiral polymer, with about 600 to 30,000 repeat units being found. Polymers with a molecular weight of at least 50,000 to about 2,000,000 are suitable for the matrix forms according to the invention, polymers with a molecular weight of at least 50,000 to about 1,500,000 being particularly preferred. The fermentative production of PHB and isolation from the cell material has been described, for example, by Lafferty et al. in Chem. Rundschau 30 (41), 14 to 16, (1977).
Ein großer Vorteil der Erfindung liegt darin, daß sich die Freisetzungsgeschwindigkeit des Wirkstoffs aus der Retardform beim erfindungsgemäßen Matrixsystem über den gewünschten Zeitraum von mehreren Stunden praktisch beliebig einstellen läßt. Der Retardeffekt ist überraschenderweise einerseits von der Korngröße der PHB und andererseits vom Gewichtsverhältnis der PHB-Matrix zum Wirkstoff, Midodrin-Hydrochlorid, abhängig. Diese Parameter werden zur Herbeiführung einer optimalen Wirkung bei der Behandlung der Hypotonie mit den erfindungsgemäßen Midodrin-Hydrochlorid-Retardformen so gewählt, daß
- a) durch Freisetzung einer ausreichenden Initialdosis innerhalb der ersten 20 - 60 Minuten nach der Verabreichung therapeutisch wirksame Blutspiegelwerte aufgebaut werden und
- b) zur Erhaltung der Blutspiegelwerte innerhalb des physiologischen Zeitraums für die Magen-Darmpassage des Präparats von etwa 4 - 12 Stunden, mit einem Optimum von etwa 6 - 10 Stunden, eine möglichst vollständige Freisetzung des Wirkstoffs unabhängig vom pH-Wert im Magen-Darmtrakt gewährleistet ist.
- a) building up therapeutically effective blood levels by releasing a sufficient initial dose within the first 20 - 60 minutes after the administration and
- b) to maintain the blood level values within the physiological period for the gastrointestinal passage of the preparation of about 4 to 12 hours, with an optimum of about 6 to 10 hours, to ensure that the active ingredient is released as completely as possible, regardless of the pH in the gastrointestinal tract is.
Midodrin-Hydrochlorid-Retardpräparate mit Freisetzungsraten, die den oben in Punkt a) und b) angegebenen Erfordernissen in jeder Weise genügen, werden unerwarteterweise nur dann erhalten, wenn man zur Retardierung als polymeres Trägermaterial eine Poly-D(-)-3-hydroxybuttersäure mit einer Korngröße von 0.05 bis 0.6 mm, vorzugsweise mit einer Korngröße von 0.2 bis 0.5 mm, verwendet und solche Mischungen aus polymerer Matrix und Wirkstoff hergestellt, die auf 1 Gew. Teil 1 bis 15 Gew. Teile, vorzugsweise jedoch 2 bis 6 Gew.Teile, ganz bevorzugt 3 bis 5 Gew.Teile PHB enthalten. Diese Mischungen werden dann zu den erfindungsgemäßen Depot-Arzneiformen verpreßt. Mit Korngrößenfraktionen, die kleiner als 0.05 mm sind, wird bei gleichen Gewichtsverhältnissen die Freisetzung des Wirkstoffs über den physiologischen Zeitraum hinaus zusätzlich verzögert. Bei Korngrößenfraktionen über 0.6 mm wird in vielen Fällen beim Preßvorgang Entmischung beobachtet, worunter die Verarbeitungsmöglichkeiten und die Dosiergenauigkeit leidet.Midodrine hydrochloride sustained-release preparations with release rates which in any way meet the requirements given in points a) and b) above are only unexpectedly obtained when a poly-D (-) - 3-hydroxybutyric acid is used as the polymeric carrier for retardation a grain size of 0.05 to 0.6 mm, preferably with a grain size of 0.2 to 0.5 mm, and such mixtures of polymeric matrix and active ingredient are produced which are 1 to 15 parts by weight, but preferably 2 to 6 parts by weight, to 1 part by weight , very preferably contain 3 to 5 parts by weight of PHB. These mixtures are then pressed into the depot dosage forms according to the invention. With grain size fractions that are smaller than 0.05 mm, the release of the active substance is delayed beyond the physiological period with the same weight ratios. In the case of grain size fractions over 0.6 mm, segregation is observed in many cases during the pressing process, which affects the processing options and the dosing accuracy.
Ist in schweren oder pathologischen Fällen von Hypotonie aus therapeutischen Gründen eine hohe Initialdosis innerhalb der ersten dreißig Minuten und eine hohe Erhaltungsdosis Über 1 bis 4 Stunden notwendig, so genügen diesem Erfordernis erfindusngsgemäße Retardformen, welche auf 1 Gew.Teil Midodrin-Hydrochlorid 1 bis 2 Gew-Teile PHB enthalten. Erfordert die Therapie andererseits nach Freisetzung der lnitialdosis die Aufrechterhaltung einer gleichmäßiger Erhaltungsdosis Über mehrere Stunden, so sind für Depot-Arzneiformen, die innerhalb von 8 bis 10 Stunden den Wirkstoff vollständig abgeben sollen, Gewichtsverhältnisse Midodrin-Hydrochlorid: PHB von 1:3 bis 1:5 empfehlenswert. Ist ausnahmsweise ein Retardierungseffekt von mehr als 10 Stunden erwünscht, konnenn auch Arzneiformen mit 6 bis 15 Gew.Teilen PHB eingesetzt werden.In severe or pathological cases of hypotension for therapeutic reasons, a high initial dose is within the first thirty minutes and one high maintenance dose necessary for 1 to 4 hours, this requirement meets inventive prolonged release forms which contain 1 to 2 parts by weight of PHB per 1 part by weight of midodrin hydrochloride. If, on the other hand, the therapy requires maintenance of a uniform maintenance dose for several hours after the initial dose has been released, the weight ratios of midodrine hydrochloride: PHB of 1: 3 to 1: for depot dosage forms which are to release the active ingredient completely within 8 to 10 hours. 5 recommended. If, exceptionally, a retardation effect of more than 10 hours is desired, drug forms with 6 to 15 parts by weight of PHB can also be used.
Midodrin-Hydrochlorid ist ein sehr wirksamer Arzneistoff, der in ausgesprochen niedrigen Dosen dem Patienten verabreicht wird. Der Dosisbereich für die erfindungsgemäßen Retardformen liegt zwischen 3.5 und 20 mg Midodrin-Hydrochlorid pro Dosiseinheit, vorzugsweise jedoch zwischen 7.5 und 15 mg. In einzelnen Fällen pathologischer Krankheitsformen kann unter ärzlicher Kontrolle ausnahmsweise ein höherer Dosisbereich pro Dosiseinheit bei der Retardform angebracht sein.Midodrin hydrochloride is a very effective drug that is administered to the patient in extremely low doses. The dose range for the slow release forms according to the invention is between 3.5 and 20 mg of midodrin hydrochloride per dose unit, but preferably between 7.5 and 15 mg. In individual cases of pathological forms of disease, a higher dose range per dose unit may exceptionally be appropriate for the slow-release form under medical supervision.
Ein weiterer Gegenstand der Erfindung ist ein Verfahren zur Herstellung dieser Midodrin-Hydrochlorid-Retardformen.Another object of the invention is a method for producing these midodrine hydrochloride sustained release forms.
Die durch Fermentation und Isolierung aus der Biomasse gewonnene PHB zeichnet sich im Gegensatz zu Polylactiden oder anderen für galenische Zwecke eingesetzten biologisch abbaubaren Polymeren durch günstige physikalische Eigenschaften wie geringe elastische Eigenschaften und geringe elektrostatische Aufladungstendenz aus, und verfügt auch über gute Schmier- und Glelteigenschaften; Daher, können die erfindungsgemaßen Retardformen sowohl in technischer als auch apparativer Hinsicht auf unerwartet einfache Art und Weise hergestellt werden.In contrast to polylactides or other biodegradable polymers used for galenical purposes, the PHB obtained from the biomass by fermentation and isolation is characterized by favorable physical properties such as low elastic properties and low electrostatic charging tendency, and also has good lubricating and glazing properties; Therefore, the slow release molds according to the invention can be produced in an unexpectedly simple manner, both from a technical and an apparatus point of view.
Das Fermentationsprodukt wird durch Malen zerkleinert und aus dem Malgut wird dann durch Siehanalyse die für die Herstellung des Homogenats gewünschte Korngrößenfraktion im Bereich von 0.05 bis 0.6 mm gewonnen.The fermentation product is crushed by painting and the grain size fraction required for the production of the homogenate in the range from 0.05 to 0.6 mm is then obtained from the material to be painted by sieve analysis.
Im einzelnen geht man beim erfindungsgemäßen Verfahren so vor, daß man den Wirkstoff auf mechanische Weise mit der PHB im gewünschten Gewichtsverhältnis vermischt und in eine homogene Form bringt.In detail, the procedure according to the invention is such that the active ingredient is mixed mechanically with the PHB in the desired weight ratio and brought into a homogeneous form.
Das Homogenisieren kann bei geringen Materialmengen zweckmäßigerweise mittels Pulverreibschale und Pistill oder einer Pulvermischdose erfolgen. Große Ansätze lassen sich vorteilhafterweise mit Hilfe von rotierenden Trommeln,Kubusmischern, Schaufelmischern, Tellermischern, Mischschnecken, Ribbonmischern, Konusmischern, Doppelkonusmischern, V-Mischern (Twin-Shell-blenden) oder ähnlichen Geräten homogenisieren.For small quantities of material, the homogenization can expediently be carried out using a powder grater and pestle or a powder mixing can. Large batches can advantageously be homogenized with the help of rotating drums, cube mixers, paddle mixers, plate mixers, mixing screws, ribbon mixers, cone mixers, double cone mixers, V mixers (twin-shell orifices) or similar devices.
Die auf diese Weise erhaltenen Homogenate werden anschließend gemäß einer bevorzugten Verfahrensmethode direkt ohne weitere Zuschlagsstoffe zu Tabletten, Drageekernen, Stäbchen oder anderen Komprimaten beliebiger Form verpreßt. Der Wirkstoff läßt sich aber auch mit PHB und gewünschtenfalls weiteren direkttablettlerbaren Hilfsstoffen, Schmiermitteln usw. zu einer direkttablettierbaren Mischung verarbeiten, die dann zu Arzneimittel-Formkörpern verpreßt wird.The homogenates obtained in this way are then pressed according to a preferred process method directly into tablets, dragee cores, sticks or other compresses of any shape without further additives. However, the active ingredient can also be processed with PHB and, if desired, other direct-tablettable auxiliaries, lubricants, etc. to form a direct-tablettable mixture which is then pressed to give shaped pharmaceutical articles.
Die Herstellung der erfindungsgemäßen Arzneimittelformkörper ist mit allen herkömmlichen, manuellen oder automatischen Pressen möglich. Der Preßdruck kann über den Bereich von 0.1 bis etwa 10 Tonnen/cm2, entsprechend 9.81 bis 981 N/mm2 beliebig variiert werden und richtet sich je nach Art und Form der hergestellten Preßlinge. Die Freisetzungsrate des Wirkstoffs weist bei einer Variation des Preßdrucks im oben angegebenen Bereich keine signifikante Abhängigkeit vom Preßdruck auf.It is possible to produce the pharmaceutical tablets according to the invention with all conventional, manual or automatic presses. The pressure can be varied over the range from 0.1 to about 10 tons / cm 2 , corresponding to 9.81 to 981 N / mm 2 , and depends on the type and shape of the compacts produced. The release rate of the active substance shows no significant dependence on the pressing pressure when the pressing pressure is varied in the range given above.
Natürlich kann man auch das Homogenat aus Wirkstoff und PHB zuerst feucht oder trocken nach einem der üblichen Granulierverfahren zu einem Granulat verarbeiten, und diese Granulate gegebenenfalls nach Zumischung von in der Galenik üblichen Hilfsstoffen zu Arzneimittel-Formkörpern verpressen. Man kann aber auch den Wirkstoff gegebenenfalls mit üblichen Hilfsstoffen zuerst durch Feucht- und Trockengranulation in ein Granulat überführen, dem nachträglich die PHB zugesetzt wird, worauf die Masse zu Arzneimittel-Formkörpern verpreßt wird. Die Anwendung solcher Granulierverfahren beinhaltet einen zusätzlichen Verfahrensschritt, bietet aber gegenüber der Direktverpressung des Homogenats keinen nennenswerten Vorteil.Of course, the homogenate of active ingredient and PHB can also first be processed moist or dry into granules using one of the customary granulation processes, and these granules, if appropriate after the addition of additives customary in galenics, can be pressed to give shaped medicinal products. However, the active ingredient can also be converted into granules, to which the PHB is subsequently added, by means of wet and dry granulation, where appropriate, after which the mass is pressed to give shaped medicinal products. The use of such granulation processes includes an additional process step, but offers no significant advantage over the direct pressing of the homogenate.
Die Einfachheit, mit der gemäß der Erfindung optimale, orale, feste Midodrin-Hydrochorid-Retardformen realisiert werden können, war nicht vorhersehbar. Zieht man die Schwierigkeiten in Betracht, die bei der Retardierung von Midodrin-Hydrochlorid bisher bestanden haben und die bei den bisher bekannten biologisch abbaubaren Matrixformen in der Arzneiformengebung auftreten, so ist es für einen Fachmann ein unerwartetes Ergebnis, daß man im erfindungsgemäßen Matrixsystem durch einfaches Mischen und Verpressen feste Retardformen von Midodrin-Hydrochlorid mit nahezu beliebig variierbaren Freisetzungsraten herstellen kann. Einen weiteren unerwarteten Vorteil bieten die erfindungsgemäßen Retardformen aber auch dadurch, daß innerihalb der ersten 20 bis 60 Minuten nach der Verabreichung die zum Aufbau von therapeutisch wirksamen Blutspiegelwerten benötigte Initialdosis des Wirkstoffs direkt aus dem Matrixsystem freigesetzt wird. Dadurch kann bei den erfindungsgemäßen Präparaten im Gegensatz zu den meisten retardierten Arzneiformen auf zusätzliche Maßnahmen , die die Freisetzung der Initialdosis gewährleisten sollen, wie beispielsweise Aufsprühen, Beschichten oder Überziehen der Retardform mit dem Wirkstoff in Instantform, verzichtet werden. Auf diese Weise können die mit solchen Maßnahmen üblicherweise einbergehenden Verluste an Wirkstoff vermieden und das Herstellungsverfahren vereinfacht werden.The simplicity with which optimal oral, solid midodrine hydrochloride prolonged release forms can be achieved according to the invention was not predictable. If one takes into account the difficulties which have hitherto existed in the retardation of midodrine hydrochloride and which occur with the previously known biodegradable matrix forms in the formulation of pharmaceutical forms, it is an unexpected result for a person skilled in the art that in the matrix system according to the invention by simple mixing and pressing can produce solid prolonged-release forms of midodrine hydrochloride with release rates that can be varied in almost any manner. However, the sustained release forms according to the invention also offer a further unexpected advantage in that within the first 20 to 60 minutes after administration, the initial dose of the active ingredient required to build up therapeutically effective blood level values is released directly from the matrix system. In contrast to most retarded medicinal forms, the preparations according to the invention can therefore dispense with additional measures which are intended to ensure the release of the initial dose, such as spraying, coating or coating the retard form with the active ingredient in instant form. In this way, the losses of active ingredient usually associated with such measures can be avoided and the manufacturing process can be simplified.
Die gleichmäßige und verzögerte Freisetzung des Wirkstoffs aus den erfindungsgemäßen Retardformen kann sowohl in Modellversuchen in vitro als auch in Tierversuchen in vivo nachgewiesen werden. So weist beispielsweise eine Midodrin-Hydrochlorid-Retardtablette gemäß der vorliegenden Erfindung, die 7.5 mg Gutron und 22.5 mg PHB mit einer Komgrößenfraktion von 0.2 bis 0.315 mm und einem Molekulargewicht von 1.06 106 in homogener Mischung enthält, im in vitro Versuch nach einer Stunde eine Freisetzungsrate von 47.33 %, entsprechend 3.5 mg Midodrin-Hydrochlorid auf, während nach 7 Stunden der Wirkstoff zu 100 % aus der Retardform freigesetzt wird. Bei in vivo-Versuchen mit einer gleichen Midodrin-Hydrochlorid-Retardtablette erhält man ähnliche Freisetzungsraten, die beispielsweise 2 Stunden nach der Verabreichung 67.65 % und 8 Stunden nach der Verabreichung 96.18 % der in der Retardform anfänglich vorhandenen Wirkstoffmenge betragen.The uniform and delayed release of the active ingredient from the slow release forms according to the invention can be demonstrated both in model experiments in vitro and in animal experiments in vivo. For example, a midodrine hydrochloride prolonged-release tablet according to the present invention, which contains 7.5 mg gutron and 22.5 mg PHB with a grain size fraction of 0.2 to 0.315 mm and a molecular weight of 1.06 10 6 in a homogeneous mixture, has one hour after in vitro experiment Release rate of 47.33%, corresponding to 3.5 mg of midodrine hydrochloride, while after 7 hours the active ingredient is released from the prolonged-release form. In vivo experiments with the same midodrin hydrochloride prolonged-release tablet give similar release rates, for example 2 hours after administration 67.65% and 8 hours after administration are 96.18% of the amount of active ingredient initially present in the sustained-release form.
Die nachfolgenden Beispiele sollen das Wesen der Erfindung erläutern, ohne sie aber zu beschränken:The following examples are intended to explain the essence of the invention, but without restricting it:
Die Bestandteile werden gesiebt vermengt und in einem Kubusmischer homogenisiert.The ingredients are sieved and mixed and homogenized in a cube mixer.
Das Homogenat wird bei einem Preßdruck von 3.2 Tonnen/cm2, entsprechend 313.92 N/mm2, zu Tabletten verpreßt.The homogenate is pressed into tablets at a pressure of 3.2 tons / cm 2 , corresponding to 313.92 N / mm 2 .
Tablettengewicht: 30 mgTablet weight: 30 mg
Tablettengröße: Durchmesser 4.0 mm, Höhe 2.0 mmTablet size: diameter 4.0 mm, height 2.0 mm
Bruchfestigkeit: 9.8 kpBreaking strength: 9.8 kp
In vitro-Wirkstofffreigabe Midodrin-Hydrochlorid:
- Bedingungen: U.S.P XX-paddle-Methode, 100 Umdrehungen/Min 37° C, physiol. NaCl lsg.
- analyt. Bestimmung: direkt spektralphotometrisch bei Lambda = 279 nm
- Conditions: USP XX paddle method, 100 revolutions / min 37 ° C, physiol. NaCl solution
- analyt. Determination: direct spectrophotometric at lambda = 279 nm
Die Freigaben in vitro wurden in den folgenden Beispielen stets unter diesen Bedingungen durchgeführt:
Die Verarbeitung zu Tabletten erfolgt analog zu Beispiel 1.
In vitro-Wirkstofffreigabe Midodrin-Hydrochlorid:
In vivo-Wirkstofffreigabe Midodrin-Hydrochlorid:In vivo drug release midodrin hydrochloride:
Die Tabletten werden Ratten mittels einer Spezialsonde peroral appliziert und die Ausstrommenge an Midodrin-Hydrochlorid zu den angegebenen Zeitpunkten (2,4,6,8 Stunden) durch Rückstandsbestimmung ermittelt. Dazu werden die Tiere mittels Nackenschlag getötet und die Tabletten aus dem Gastrointestinaltrakt entnommen. Nach Reinigung und Trocknung der Tabletten werden diese mechanisch zerkleinert, mit H20 versetzt und im Ultraschallbad zur vollständigen Freisetzung von Midodrin-Hydrochlorid weiterbehandelt. Nach dem Zentrifugieren wird Midodrin-Hydrochlorid direkt aus der Lösung bestimmt.
Die Verarbeitung zu Tabletten erfolgt analog zu Beispiel 1 unter verschiedenen Preßdrucken.
In vitro Wirkstofffreigabe Midodrin-Hydrochlorid:
Die Freisetzungsraten sind vom Preßdruck im Bereich von 0.5 bis 2.0 Ton- nen/cm2, mit dem das Homogenat in Beispiel 3 zu Tabletten verpreßt wurde, unabhängig.The release rates are independent of the pressure in the range from 0.5 to 2.0 tons / cm 2 , with which the homogenate in Example 3 was pressed into tablets.
Die Verarbeitung zu Tabletten erfolgt analog zu Beispiel 1.
In vitro Wirkstoffireigabe Midodrin-Hydrochlorid:
Die Verarbeitung zu Tabletten erfolgt analog zu Beispiel 1.
In vitro Wirkstofffreigabe Midodrin-Hydrochlorid:
Die Verarbeitung zu Tabletten erfolgt analog zu Beispiel 1.
In vitro Wirkstofffreigabe Midodrin-Hydrochlorid:
In vitro Wirkstofffreigabe Midodrin-Hydrochlorid:
Die Verarbeitung zu Tabletten erfolgt analog zu Beispiel 1.
In vitro Wirkstofffreigabe Midodrin-Hydrochlorid:
Claims (9)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT85105612T ATE54049T1 (en) | 1984-05-11 | 1985-05-08 | RETARDED FORMS OF ALPHA-(2,5-DIMETHOXY-PHENYL)-BETA-LYCINAMIDO-AETHANOL AND PROCESS FOR THEIR PRODUCTION. |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3417576 | 1984-05-11 | ||
| DE19843417576 DE3417576A1 (en) | 1984-05-11 | 1984-05-11 | RETARD FORMS OF ALPHA- (2,5-DIMETHOXY-PHENYL) -SS-GLYCINAMIDOAETHANOL AND METHOD FOR THE PRODUCTION THEREOF |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| EP0164571A2 true EP0164571A2 (en) | 1985-12-18 |
| EP0164571A3 EP0164571A3 (en) | 1987-04-22 |
| EP0164571B1 EP0164571B1 (en) | 1990-06-27 |
Family
ID=6235629
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP85105612A Expired - Lifetime EP0164571B1 (en) | 1984-05-11 | 1985-05-08 | Sustained-release forms of alpha-(2,5-dimethoxy phenyl)-beta-glycinamidoethanol and process for their preparation |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0164571B1 (en) |
| AT (1) | ATE54049T1 (en) |
| CS (1) | CS332091A3 (en) |
| DE (2) | DE3417576A1 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4902516A (en) * | 1987-04-10 | 1990-02-20 | Chemie Holding Aktiengesellschaft | Binder-free granules with delayed release of the active compound |
| US5128144A (en) * | 1989-10-16 | 1992-07-07 | Pcd Polymere Gesellschaft M.B.H. | Pressing having sustained release of active compound |
| WO2001074335A1 (en) * | 2000-03-31 | 2001-10-11 | Nycomed Austria Gmbh | Pharmaceutical kit comprising midodrine as an active drug substance |
| WO2001074334A1 (en) * | 2000-03-31 | 2001-10-11 | Nycomed Austria Gmbh | Controlled release pharmaceutical composition containing midodrine and/or desglymidodrine |
| US6761904B2 (en) | 2000-03-31 | 2004-07-13 | Nycomed Austria Gmbh | Pharmaceutical kit comprising midodrine as active drug substance |
| US7070803B2 (en) | 2000-03-31 | 2006-07-04 | Nycomed Austria Gmbh | Controlled release pharmaceutical composition for oral use containing midodrine and/or active metabolite, desglymidodrine |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3935736A1 (en) * | 1989-10-27 | 1991-05-02 | Chemie Linz Deutschland | Pressed article for sustained pharmaceutical release - contg. poly-lactic acid and polymer of D-3-hydroxybutyric acid, providing good flow properties and easy compression |
| EP0429832B1 (en) * | 1989-11-30 | 1994-06-22 | PCD-Polymere Gesellschaft m.b.H. | Pressed core without sustained drug release, process for its preparation and use of polyhydroxybutyric acid for making such a pressed core |
| DE4000155A1 (en) * | 1990-01-04 | 1991-07-11 | Chemie Linz Deutschland | Pressed tablet for oral admin. with non-retarded release of agent - comprises homo and/or copolymer of D-(-)-3-hydroxybutyric acid, disintegrating and active-agents and has good storage stability |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH649217A5 (en) * | 1977-08-25 | 1985-05-15 | Sandoz Ag | BROMOCRIPTIN CONTAINING MICROCAPSULES. |
| DE2824112A1 (en) * | 1978-06-01 | 1979-12-06 | Garching Instrumente | Micro-pellets of biodegradable polymeric carrier - esp. poly:hydroxy-carboxylic acid, and active ingredient e.g. narcotic antagonist |
| AT382076B (en) * | 1982-10-15 | 1987-01-12 | Chemie Linz Ag | METHOD FOR THE PRODUCTION OF PRESSURES WITH RETARDED ACTIVE SUBSTANCE RELEASE |
-
1984
- 1984-05-11 DE DE19843417576 patent/DE3417576A1/en not_active Withdrawn
-
1985
- 1985-05-08 AT AT85105612T patent/ATE54049T1/en not_active IP Right Cessation
- 1985-05-08 EP EP85105612A patent/EP0164571B1/en not_active Expired - Lifetime
- 1985-05-08 DE DE8585105612T patent/DE3578372D1/en not_active Expired - Fee Related
-
1991
- 1991-11-01 CS CS913320A patent/CS332091A3/en unknown
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4902516A (en) * | 1987-04-10 | 1990-02-20 | Chemie Holding Aktiengesellschaft | Binder-free granules with delayed release of the active compound |
| US5128144A (en) * | 1989-10-16 | 1992-07-07 | Pcd Polymere Gesellschaft M.B.H. | Pressing having sustained release of active compound |
| WO2001074335A1 (en) * | 2000-03-31 | 2001-10-11 | Nycomed Austria Gmbh | Pharmaceutical kit comprising midodrine as an active drug substance |
| WO2001074334A1 (en) * | 2000-03-31 | 2001-10-11 | Nycomed Austria Gmbh | Controlled release pharmaceutical composition containing midodrine and/or desglymidodrine |
| US6761904B2 (en) | 2000-03-31 | 2004-07-13 | Nycomed Austria Gmbh | Pharmaceutical kit comprising midodrine as active drug substance |
| US7070803B2 (en) | 2000-03-31 | 2006-07-04 | Nycomed Austria Gmbh | Controlled release pharmaceutical composition for oral use containing midodrine and/or active metabolite, desglymidodrine |
Also Published As
| Publication number | Publication date |
|---|---|
| CS332091A3 (en) | 1992-04-15 |
| EP0164571B1 (en) | 1990-06-27 |
| EP0164571A3 (en) | 1987-04-22 |
| DE3417576A1 (en) | 1985-11-14 |
| ATE54049T1 (en) | 1990-07-15 |
| DE3578372D1 (en) | 1990-08-02 |
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